The objective of this application is to understand the neuroendocrine and immunological mechanisms underlying the modulatory effects of the estrous cycle, gonadal hormones, and gender on immune competence and tumor development. The immune and the neuroendocrine systems regulate each other. In addition to sex hormone secretion, many neuroendocrine responses, e.g., stress responses, are known to be sexually dimorphic, therefore, suggesting mechanisms underlying sexual dimorphism of immunity and tumor susceptibility. Clinical observations report up to a three fold increase in the rate of long-term mortality due to tumor recurrence in women undergoing mastectomy during the high estrogen-low progesterone phase of their menstrual cycle. Using an animal model of breast cancer metastasis, the investigators have observed a large decline in the ability of the host to prevent metastases during estrous phases of the F344 rats that are hormonally homologous to the high risk period reported in women. They therefore hypothesize that the clinical observations are attributable to a decrease in the host resistance to mastectomy-induced tumor dissemination, a decrease caused by suppressive effects of sex hormones on innate immunity. The proposed studies will use the F344 rat to address biomedical issues relevant to human health, and are designed with the following three specific aims: (1) To elucidate hormonal mediators of the estrous cycle effects they have observed, particularly the role of estradiol, progesterone, and prolactin; (2) To test the hypothesis that alteration in natural-killer (NK) cell activity, induced by sex steroids or prolactin, underlies the estrous cycle effect on the metastatic process, and to study possible cellular mechanisms by which these hormones affect NK activity; and (3) to study and distinguish between the effects that gender, long-term exposure to gonadal steroids or prolactin, and chronological age have on functional decline of NK cell activity. The investigators believe that findings from these studies will provide significant new information to improve health strategies for enhancing the survival of cancer patients.